The ideal anti-cancer drug would kill cancer cells efficiently without toxic effects on normal cells. Conventional chemotherapy drugs fall far short of this ideal. Variagenics is developing a new approach to cancer therapy which targets absolute and irreversible genetic differences between cancer and normal cells which arise as a consequence of chromosome loss in cancer cells. The resulting unequal genetic constitution of cancer cells and normal cells opens a path to the development of selectively cytotoxic drugs. The therapeutic strategy entails (i) identifying heterozygotes of a target gene which is both essential for cell survival and located on a chromosome which is frequently deleted in cancers, (ii) determining which allele is absent from a specific patients cancer cells and (iii) treating patients with an inhibitor directed to the sole allele retained by cancer cells. This allele is, of course, also present in normal cells, but normal cells (unlike cancer cells) also contain a 2nd allele, not inhibited by the allele specific inhibitor. Replication Protein A is a highly conserved protein which Variagenics has shown to be polymorphic, essential for cell survival and frequently reduced to one copy in cancer cells. This grant proposes a series of functional and structural studies of RPA that will allow it to be evaluated as a small molecule target. PROPOSED COMMERCIAL APPLICATION Effective therapy is not available for most solid cancers. Variagenices is developing a new class of cancer-specific therapeutic inhibitors, by exploiting allele loss in cancer cells. Allele specific inhibitors of RPA would be useful in treating the greater of 50 percent of solid tumors with chromosome 17p allele loss. The market for an inhibitor of one allele of RPA would be greater than 750MM for the 3 leading cancer types alone.